Making a Difference

Michigan has been pushing forward the field of biomedical engineering for over 50 years, with incredible technological contributions like ECMO, the silicon neural probe, and the spherocentric knee, to the world-class education of today’s top biomedical engineering minds.

Giant leaps forward in biomedical engineering are truly possibly when engineers and clinicians are given the environment to work in close proximity. From an engineered scaffold to aid in the early detection of breast cancer metastasis, to a controlled form of ultrasound to non-invasively destroy bad tissue in the body, to a determined mission to enable neural control of prosthetics, Michigan Biomedical Engineering is developing incredible solutions to the worlds most pressing biological and medical challenges.

Biomedical Engineering at the University of Michigan is poised to make incredible impact in the fields of engineering, biology and medicine in the years and decades ahead, from innovations in undergraduate and graduate education to groundbreaking research.

In a breakthrough that could one day lead to new treatments for lung diseases like asthma and lung cancer, researchers have successfully coaxed stem cells—the body’s master cells—to grow into three-dimensional lung tissue. This could be useful in future cell-based therapies that repair damaged lungs by cultivating new, healthy tissue.

University of Michigan researchers grew the tissue by injecting stem cells into a specially developed biodegradable scaffold, then implanting the device in mice, where the cells grew and matured into lung tissue. The team’s findings were published in the Nov. 1 issue of the journal eLife.

Briana Dye, a PhD candidate in Cell & Developmental Biology at the University of Michigan Medical School, demonstrates the process of developing lung organoid tissue samples. This research was conducted partly in the lab of Lonnie Shea, the William and Valerie Hall Department Chair and Professor of Biomedical Engineering. Photo: Evan Dougherty, Michigan Engineering Communications & Marketing

Respiratory diseases account for nearly 1 in 5 deaths worldwide, and lung cancer survival rates remain low despite numerous therapeutic advances during the past 30 years. Cell-based therapies could be a key to improving treatment, helping damaged lungs heal in much the same way as a bone marrow transplant can treat leukemia. But the complexity of lung tissue makes such treatments much more difficult to develop.

“Lung tissue needs to be able to form into specific structures like airways and bronchi, and they all need to be able to work together inside the lung. So we can’t just add in healthy adult cells,” said Lonnie Shea, the William and Valerie Hall Department Chair of Biomedical Engineering and a professor of biomedical engineering at U-M. “Instead, we’re looking at delivering the precursors to these cells, then giving them the cues they need to develop and mature on their own. This project was a step in that direction.”

While previous experiments had successfully grown lung cells, the cells were immature and disorganized. So Shea worked with a U-M medical school team led by Briana Dye, a graduate student in the U-M Department of Cell and Developmental Biology, on a new approach. They developed a three-dimensional, biodegradable scaffold that helped the lung cells mature and begin to develop into structures like those inside an actual lung.

Made of PLG, a spongy, biodegradable material, the scaffold was shaped like a small cylinder approximately five millimeters wide and two millimeters tall. The team injected stem cells into the scaffold, transplanted it into mice, then allowed the cells to mature for eight weeks.

The scaffold provided a stiff structure that supported growth of the mini lungs after transplantation while still allowing the transplanted tissue to become vascularized, growing blood vessels that supplied it with nutrients.

When the team examined the tissue, they found that it had not only survived, it had developed tube-shaped airway structures similar to the airways in adult lungs. It also developed mucus-producing cells, multiciliated cells and stem cells similar to those found in adult lungs.

“In many ways, the tissue grown in the study was indistinguishable from human adult tissue,” says senior study author Jason Spence, Ph.D., associate professor in the U-M Department of Internal Medicine and the Department of Cell and Developmental Biology at the U-M Medical School.

The researchers caution that they’re far from growing anything like a complete human lung—the tissue grown in the experiment was a mass of lung cells scattered among other types of cells inside the scaffold. But they say it’s an important early step that can yield valuable information about how healthy cells grow and develop. In the future, that could lead to new treatments for lung disease.

Richard Youngblood, a second year PhD student in Biomedical Engineering at the University of Michigan, demonstrates the construction of a lung organoid PLG scaffold. This research was conducted partly in the lab of Lonnie Shea, the William and Valerie Hall Department Chair and Professor of Biomedical Engineering. Photo: Evan Dougherty, Michigan Engineering Communications & Marketing

“What if we could regrow a portion of a damaged lung, like a patch?” Shea said. “Treatments like that, while challenging, may be possible.”

The lung tissue is one of several types of cultured organ tissue, or “organoids” that U-M research teams have developed—other cell types they’ve created include intestines, pancreatic cells and placenta cells. In addition to their uses in developing new cell-based therapy, Shea says the cells can provide a human model for screening drugs, studying gene function, generating transplantable tissue and studying complex human diseases like asthma.

“Organoids enable us to see the development and formation of an organ without having to conduct a test on an entire organism. And once we understand that, we can find new ways of repairing organs that are injured, or that haven’t developed properly.”

The paper is titled “A bioengineered niche promotes in vivo engraftment and maturation of pluripotent stem cell derived human lung organoids.” The research was supported by the National Institutes of Health (grant number R01 HL119215), by the NIH Cellular and Molecular Biology training grant at Michigan and by the U-M Tissue Engineering and Regeneration Training Grant.

Today, with over 100 members on more than nine teams working on projects for communities worldwide, it’s no surprise M-HEAL has grown significantly over the past decade.

With growth has come increased interest among members to pursue the College’s Multidisciplinary Design Minor, which enables M-HEAL students to pursue academic credit for their project work. The trend has highlighted the need for additional mentorship to help students take their projects and products to the next level, so designs can be finalized, manufactured, and adopted by end users.

“Given the large number of design teams and students interested in the Multidisciplinary Design minor and the diversity of M-HEAL projects, students are best served if they can reach out to industry experts to help them navigate many of the key aspects of solution development – ideation, design, quality, risk management, and even business development,” says Aileen Huang-Saad, M-HEAL faculty advisor since 2007, assistant professor in biomedical engineering, entrepreneurship and engineering education.

The need has led to a budding mentorship program with medical device manufacturer Stryker Corporation. Following a successful pilot with Stryker Principal Engineer, Bill Hassler, and U-M mechanical engineering and design science graduate student, Michael Deininger, in the Winter 2016 semester, the program expanded quickly.

In Fall 2016, six Stryker engineering mentors – Bruce Henniges, Mitch Baldwin, CliffLambarth, Brian VanderWoude, SteveCarusillo and Dan McCombs – began working with several M-HEAL teams, offering dozens of students access to experts with industry experience and technical skills demanded by the complex design process. With the success of the program, M-Heal students added a local business mentor, Randy Schwemmin, in Winter 2017.

Teams typically meet with mentors via Skype every two weeks to discuss progress, challenges, and next steps. Both mentors and mentees are benefiting in big ways, and the model program is expanding to other industry participants as well.

“It’s so critically important our students have this input,” says Huang-Saad. “The more resources they can draw upon to help them design better products, the better they’re able to meet the needs of their intended end users. The teams’ mentors have helped them make great progress toward their respective goals.”

Stryker mentor Bill Hassler worked with Project MESA, a portable gynecological exam table for use in Nicaragua.

“Working with bright, motivated students who are doing good work for people who need help was an honor, and it was gratifying to see that my experience could have a positive impact and help them become even more knowledgeable and enthusiastic about their project,” – Bill Hassler

“Working with bright, motivated students who are doing good work for people who need help was an honor, and it was gratifying to see that my experience could have a positive impact and help them become even more knowledgeable and enthusiastic about their project,” says Hassler.

Getting to know those motivated, bright students also introduces the company to promising talent and aids recruitment efforts. “It’s a real win-win-win,” he adds. “The program has a very good vibe around here.”

Team: PeriOperative

Mission: To provide low-resource settings with a sustainable, user-friendly warming device to keep patients at a stable core body temperature during surgery while also reducing the risk of infection.

Mentor: Bruce Henniges

Next stop: Dominican Republic, May 2018

The team is currently prototyping and finishing the design of its second iteration warming device. Using input from clinical partners in the Dominican Republic, the team has been testing new ideas for the next prototype. The team’s regulatory group is investigating CE Mark designation and performing risk analysis, according to PeriOperative team member Hannah Soifer, rising senior and former M-HEAL secretary.

Team PeriOperative worked with Stryker mentor Bruce Henniges, senior director of advanced development, who helped with the risk analysis. “This was new territory for the team this semester, and Bruce spent a lot of time explaining the best way to go about conducting it,” says Soifer. He also helped the team with schematics to make a constant current source, “something we hadn’t known how to do before,” she adds.

Working with its Stryker mentor, the team “made faster progress because we were guided in the right direction from the get-go and our potential mistakes were caught early,” Soifer says. “Bruce brought an incredible knowledge base in all areas of design and development, and he always gave us advice or resources we hadn’t known about.”

Team: Project MESA

Mission: To design a portable gynecological exam table to help improve cancer screening and better monitor pregnancies in women at high risk of complications

Mentors: Dan McCombs, Cliff Lambarth, Randy Schwemmin

Next stop: Nicaragua, May 2017

Four members of M-HEAL’s Project MESA help a nurse try on their gamma prototype of a portable gynecological examination table at their partner clinic of Santa Lastenia in Nicaragua. Credit: Jennifer Lee

The team is currently working on its sixth prototype. Members will return to Nicaragua this spring to meet with its clinical partners and get additional feedback on two prototypes, each with different features, so it can solidify the design. Members will also get feedback on two prototype tables it previously delivered, which have been in use with patients in-clinic, according to team member Samantha Fox, a rising junior.

“He really forced us to think about design decisions we’d made and their justification. He analyzed our design – and pushed us to analyze it – and opened our eyes to changes we needed to make,” Fox says.

“His experience and technical knowledge made him able to immediately see things we didn’t, and he also emphasized justifying our decisions. We have really good documentation now of the decisions we made and why, and that’s going to help us move forward,” she adds.

Team: Solar Fridge

Mission: To design an absorption refrigerator that uses solar energy to help rural health clinics and traveling health workers keep vaccines at a consistent, desired temperature.

Mentor: Steve Carusillo

Next stop: Dominican Republic, August 2017

The team has been designing and building a prototype that could be built by users on site and running evaporation tests. Members will travel to the Dominican Republic this summer to conduct a needs assessment in a local community, recommended by M-HEAL alum Hope Tambala (Chemistry, ’15), now serving as a Peace Corps volunteer in the country.

The team worked with Stryker mentor Steve Carusillo, vice president of research and development technology, who has been helping the technical team test components and develop ideas for redesigning the device for the new stakeholder community, according to team member Michelle Ruffino, rising senior.

“It’s been a very valuable interaction,” Ruffino says. “About two weeks ago I was telling Steve about issues a sub-team was having – we’re not getting enough heat transfer from the copper pipe to the condenser – and he told us to try thermal epoxy. We bought some, tested it, and we’re very likely going to implement it. It’s inexpensive and easy to use. It’s that kind of real-world expertise and experience that helps us so much,” she adds.

Team: The Initiative

Mission: To reduce infant mortality with a low-cost warmer that combines kangaroo care with an infant incubator.

Mentors: Brian VanderWoude, Mitch Baldwin

Next stop: Ethiopia, August 2017

Members of The Initiative, (left to right) Elizabeth Zwier, Elizabeth Zwier, Meghna Menon, David Chang, and Connor Yako, show Stryker mentor Brian VanderWoude (right) how to properly wear the kangaroo mother component of their hybrid infant incubator.

The team recently completed its third prototype, which includes a heated mattress, a bassinet, and a wearable wrap to hold the infant against the parent. Members plan to travel to Ethiopia this summer to further evaluate the hospital environment, conduct usability studies, and meet with its community partners.

Working with Stryker mentors “definitely helped speed up our project timelines,” said team lead Connor Yako. Mentors provided technical expertise, including feedback on materials and manufacturability, as well as big-picture input. “Having that industry experience helped us avoid power consumption and other problems we might have encountered down the line; it helped us pick the right paths early on.”

Excited by the opportunity to improve access to healthcare in a developing area of the world, Brian Vanderwoude, principal engineer with Stryker, said the team’s “creativity and resourcefulness were apparent” despite limited resources. “They weren’t intimidated by challenges, and they were really open to learning.”

What’s better than one Michigan Engineer making critical innovations at the Food and Drug Administration (FDA)? How about two?

In the fall of 2007, after earning their bachelor’s degrees in mechanical engineering at the University of Maryland Baltimore County, identical twins Aftin and Astin Ross joined U-M’s biomedical engineering master’s program. They were eager to apply their longstanding interest in science to improve the quality of people’s lives.

Flash forward 10 years later: They both went on to earn PhDs in biomedical engineering from U-M and are using their degrees to advance public health in the FDA’s Center for Devices and Radiological Health (CDRH). Between the two of them, they’ve exerted influence on the FDA’s research itself and the way the organization manages its projects and communications. Although Aftin and Astin didn’t initially plan to come to the same center, and actually followed diverging paths for a few years after obtaining their Michigan doctorates, they have been brought back together again.

After graduating from U-M in 2012, Aftin performed research at The Karlsruhe Institute of Technology in Germany. She joined the FDA in 2013 as a Commissioner’s Fellow in emergency operations involving medical device availability and delivery. Now as a Senior Project Manager, she continues to provide engineering expertise for a preparedness program that makes sure patients have access to medical devices during emergencies like disease outbreaks or radiological events. She also aids in incident response for medical device public health concerns and is working to develop policy for medical device cybersecurity.

“We want to make our decisions based on science — that’s a key part of what we do at the FDA. I can put a huge technical background into the work I do, and I’m then able to use that to make broader, more immediate impacts. It is a wonderful feeling to know that the projects that I work on have helped enhance or even saved people’s lives.”

Her work in Germany also gave her a cross-cultural understanding of scientific approaches to global issues that she works with now. “These issues that are happening in the United States are not just happening here. They also have global impact,” she points out.

After graduating from U-M in 2014, Astin worked as an editor for Cactus Communications and as a researcher for the National Institute on Deafness and Communication Disorders at the National Institutes of Health, before getting a call from the FDA asking her to join as a Staff Fellow in 2016.

Now, a Senior Science Health Advisor, she manages two main projects at the FDA. She is coordinating the implementation and continuous improvement of an internal regulatory science review process that fosters more collaborative relationships between researchers and regulatory reviewers in CDRH. This is done by providing the opportunity for people with similar scientific and clinical interests to interact in-person and use human centered design approaches to brainstorm ways to enhance regulatory science research. She has also been instrumental in launching a program that serves as an all-inclusive resource for various groups working on issues with broad impact across CDRH, enabling FDA employees to understand which experts are already working in a given area and where there may be gaps that they might address by starting new project groups.

“What really attracted me to come here was that, although I enjoyed research, it took a long time to see the application of my work. Coming into a position like this, I can see the application and visibility of my impact. To coordinate and improve the way people work effectively at the FDA, which in itself improves public health, is really powerful.”

During graduate school, Aftin and Astin had been involved in many of the same extracurriculars, including the Society of Minority Engineers and Scientists – Graduate Component (SMES-G) and the Movement of Underrepresented Sisters in Engineering and the Sciences (MUSES).

Their graduate studies, coupled with their activities outside of class, have given them a boost in collaborating, organizing, leading and networking in their current roles. “Working with people with different personalities, and various nationalities and cultural perspectives at Michigan was extremely valuable,” Astin says.

It doesn’t hurt that Aftin and Astin have been surrounded by Michigan alums at their organizations post-graduation — the shared experience has been a jumping off point for countless new conversations and collaborations.

ANN ARBOR—The Rehabilitation Biomechanics Laboratory at the University of Michigan looks part playground, part film studio, part bionic woman.

A mechanical foot sliced off cleanly at the ankle sits on a shelf—a prosthesis for testing. Twenty cameras on tripods of various heights are aimed toward the center of the room at a cluster of random objects: A door that opens into nothing. A desk phone on a table. A pitcher of water and a glass. A chair. A long, shallow sandbox.

Actually, these objects aren't random at all, explains U-M doctoral student Susannah Engdahl. They've been carefully selected to measure and compare the range of motion of people who use prosthetics against those who don't.

This is Engdahl's area of research, and her own disability has proven helpful in setting up these experiments. Engdahl is missing both hands and most of both feet.

She shrugs and sips her coffee:

"I was born this way. The doctors never nailed down a cause."

Engdahl, 25, earned her bachelor's degree at Wittenberg University in Ohio, and says she decided on the U-M program in biomedical engineering because it "hit all the checkmarks"—health, math, science and the human body.

"Biomedical engineering is a broad field and prosthetics stood out because I already knew how important prosthetics can be in improving quality of life," Engdahl says.

She has been in U-M faculty member Deanna Gates' Rehabilitation Biomechanics Laboratory for three years. Part of the School of Kinesiology, the lab is tucked in the basement of the Central Campus Recreation Building in a converted racquetball court that still feels faintly humid.

Susannah Engdahl, biomedical engineering doctoral student, opens a prop door in the Biomechanics Laboratory, where experiments are conducted to record muscle movement. Image credit: Austin Thomason, Michigan PhotographyEngdahl has been lucky with her own prosthetic hands, she says, because she's had very little pain or awkwardness, which is a huge problem among prosthetic users. Hers is among the family of prosthetics called myoelectric, which work by capturing electrical signals from the body—in this case, her arms—to control her hands.

Other prosthetics are body powered—they're held to the body by harnesses and move when cables are activated by body movement. Each has advantages and disadvantages, but one big upside of Engdahl's is that at first glance you don't even know she's wearing them. She received her first pair of prosthetics when she was about 2.

"The cosmetic factor probably helped my parents make that decision," Engdahl says, contemplating the flesh-colored stretchy sleeve that encases the hard plastic shell protecting the tiny electronics and motors that move the fingers of her hands.

But despite their natural look, the prosthetics can move only in one direction. The hands open with the thumb moving in opposition to the fingers, and close with the thumb moving towards the fingers. The thumb, index finger, and middle finger come together to create a "tripod" grip.

"Developing prosthetics that can move more similarly to a natural hand is an active area of research," Engdahl says, gripping her cardboard cup.

Quantifying how people use different types of prosthetics is one of Engdahl's dissertation research projects, and a career interest.

"It's important because most of the current research on prosthetic function is from patient feedback," says Gates, lab director and assistant professor with appointments in kinesiology and biomedical engineering.

"There's no clear direction to focus on improvements in quality of movement or range of motion, and no clear way to convince insurance companies to pay for advanced prosthetic devices."

It's natural to wonder how people with prosthetics perform everyday tasks: How do you type? Open doors? Tie your shoes? Engdahl doesn't even think about her own work-arounds, but compensations are a part of life for any prosthetic user.

Engdahl demonstrates one of these adaptations when she opens the prop door in the lab.

"It's hard for me to stand in front of the door, so I take a step over," she says. She doesn't have any wrist motion, so she moves slightly to one side of the knob for leverage, then turns the handle.

From real life to research to teaching

Engdahl not only uses her experiences with limb loss to inform her research, she also parlays them into teaching opportunities to spark future scientists. Every year, she helps Gates with the annual FEMMES event, which stands for Females Excelling More in Math, Engineering and the Sciences.

"We show the girls how the brain sends signals to muscles and how these can be measured and then used to control prosthetics," Gates says. "Susannah is generous enough to bring in one of her old sets of hands for the girls to try and she shows them how she uses them to do different things."

The girls spend the day measuring their muscle activity and making moveable hands of paper, string and straws.

"It's a great event that wouldn't be possible if Susannah weren't so open to talking with the girls about her experiences," Gates says.

When asked whether she's naturally optimistic, Engdahl says it's not easy to compare people in terms of "getting past" issues. She's always had access to the best health care and a supportive family, so it could be much simpler for her to overcome something that's difficult for someone without those advantages, she says.

"Although it did take me awhile to figure out all the tricks of the trade, I've found that most of the things I need to do in daily life can be accomplished with patience and creativity," Engdahl says. "I don't have a reason to feel intimidated by physical barriers because I'm usually able to find solutions. Admittedly, sometimes my solutions aren't ideal. But self-sufficiency is important to me, and I'd rather get a task done slowly than just not do it at all."

by Aimee Balfe

“We’re now using virtual surgical planning in the clinical realm, not as a retrospective theoretical exercise,” says Figueroa.

Using patients’ medical and imaging data, Figueroa can create a model of their unique vasculature and blood flow, then use it to guide surgeons and cardiologists through specific operations and procedures. One type of procedure involves placing grafts in the inferior vena cava to help alleviate complications from pulmonary arteriovenous malformations (PAVMs).

“We’re now using VIRTUAL SURGICAL PLANNING in the clinical realm, NOT AS A RETROSPECTIVE THEORETICAL EXERCISE.” Alberto Figueroa

PAVMs – abnormal connections between a patient’s veins and arteries – are a common complication of a procedure performed early in the lives of children born with only a single functioning ventricle. Called the Fontan procedure, the operation rewires patients’ pulmonary circulation so that the venous return bypasses the heart and is connected directly to the pulmonary arteries for transport to the lungs.

While these surgeries can be lifesavers, the long-term consequences depend heavily on how evenly blood flow is distributed between a patient’s lungs. Patients with ideal hemodynamics do well; those with less-than-perfect flow patterns suffer a sting of life-threatening complications, such as low blood oxygen and elevated cardiac output.

Figueroa’s technique can help those with complications by better balancing flow to the lungs.

Simulation & Outcome: A Perfect Match

“What we bring to the table in operations like this is, instead of going in blind, we can simulate multiple different ways of doing the procedure to see if there is an optimal one.”

Figueroa makes use of detailed anatomical data such as CT scans, Doppler data on velocity in various vessels, invasive catheterization data that shows pressures at multiple locations, and perfusion data from nuclear medicine tests. His lab creates hemodynamic models of each patient that match these data points precisely. They then simulate multiple different ways of placing a stent graft using U-M's high performance Flux computing cluster, provided by Advanced Research Computing, to identify the best outcome.

“During these procedures, the surgeons use angiograms to illuminate the blood flow,” says Figueroa. “This has shown that the results match what our computer simulation predicted.” (See image.)

“The clinicians were amazed, but we told them we were just solving Newton’s law.” Alberto Figueroa

Before (left) and after (right) images from an angiogram (top) and a surgical simulation (bottom). Note the tight correlation between the simulations and angiograms as well as the significantly more even distribution of hepatic venous flow between the two lungs after a simulation-guided procedure. Credit: Kevin Lau, Alberto Figueroa.

Better Primary Surgeries

In addition to corrective surgeries, these simulation techniques can also allow surgeons to optimize initial procedures like the Fontan so that complications may never happen at all.

Of the tens of thousands of patients undergoing Fontan operations each year, he says, roughly half experience major complications after 10 years. That’s because it’s almost impossible for surgeons to know exactly how to perform the procedure on patients with vessels of various sizes, shapes, and flows.

By accounting for these differences, Figueroa hopes his simulations will show surgeons where in the vasculature to make the surgical connections so that blood flow is ideally balanced between the lungs in each patient. He plans to work with U-M colleagues on patient-specific Fontan planning.

And because his simulations add a layer of insight to any procedure where cardiologists and surgeons find that doing things the same way works in some patients and not others, Figueroa hopes they’ll soon become a ubiquitous precision planning tool, much like imaging is today.

Additional Applications

As promising as it is, surgical planning is only the tip of the iceberg for Figueroa. His lab also works to further develop its simulation software and to use it to understand disease progression, always with an eye toward devising better treatments.

In the software arena, his lab is working on enhancements that will account for dynamic changes in blood flow caused by anything from a change in posture to anesthesia.

One of the lab’s clinical fellows is studying how blood vessels remodel in response to the grafts used in thoracic aneurysm repair. Another is modeling aortic dissection, aiming to discover precisely how the flap that shears from the vessel wall moves, deforms the aorta, and affects blood flow. This understanding is a first step toward designing a device specifically for this condition.

His lab also hosts BME students who are developing tools to better understand blood flow in the brain, clot-development in veins, and the progression of hypertension, including which types of vessels sustain various degrees of damage over time. Figueroa has recently submitted a collaborative grant to explore the progression of pulmonary hypertension, as well.

The breadth and clinical relevance of his work are in many ways why Figueroa came to U-M from King’s College, London, two years ago. Named the Edward B. Diethrich M.D. Research Professor of Biomedical Engineering and Vascular Surgery, Figueroa, a PhD, was drawn by his 50/50 appointment in BME and vascular surgery at an institution where medicine and engineering are deeply integrated.

It’s because of this connection that rapid-response surgical planning is made possible, he says. It’s also given him ready access to talented students from the medical and engineering schools – and to usually hard-to-reach study participants, like aortic dissection patients, to gain critical insight into this and other life-threatening conditions.

A team of researchers at the University of Michigan has developed a new, revolutionary technique that has the potential to reshape the practice of surgery. Histotripsy — literally, the “crushing of tissue” — is a noninvasive therapy that uses high-intensity ultrasound pulses to liquify tissue inside the body without ever breaking the skin. With applications from congenital heart defects to brain tumors, Histotripsy will significantly impact quality of life for patients, who will be able to receive it at their physician’s office — potentially at the exact time of diagnosis — without sedation or a lengthy recovery.

University of Michigan researchers have used a “kidney on a chip” device to mimic the flow of medication through human kidneys and measure its effect on kidney cells. The new technique could lead to more precise dosing of drugs, including some potentially toxic medicines often delivered in intensive care units.

Precise dosing in intensive care units is critical, as up to two-thirds of patients in the ICU experience serious kidney injury. Medications contribute to this injury in more than 20 percent of cases, largely because many intensive care drugs are potentially dangerous to the kidneys.

Determining a safe dosage, however, can be surprisingly difficult. Today, doctors and drug developers rely mainly on animal testing to measure the toxicity of drugs and determine safe doses. But animals process medications more quickly than humans, making it difficult to interpret test results and sometimes leading researchers to underestimate toxicity.

The new technique offers a more accurate way to test medications, closely replicating the environment inside a human kidney. It uses a microfluidic chip device to deliver a precise flow of medication across cultured kidney cells. This is believed to be the first time such a device has been used to study how a medication behaves in the body over time, called its “pharmacokinetic profile.”

“When you administer a drug, its concentration goes up quickly and it’s gradually filtered out as it flows through the kidneys,” said University of Michigan Biomedical Engineering professor Shuichi Takayama, an author on the paper. “A kidney on a chip enables us to simulate that filtering process, providing a much more accurate way to study how medications behave in the body.”

Takayama said the use of an artificial device provides the opportunity to run test after test in a controlled environment. It also enables researchers to alter the flow through the device to simulate varying levels of kidney function.

“Even the same dose of the same drug can have very different effects on the kidneys and other organs, depending on how it’s administered,” said Sejoong Kim, an associate professor at Korea’s Seoul national University Budang Hospital, former U-M researcher and author on the paper. “This device provides a uniform, inexpensive way to capture data that more accurately reflects actual human patients.”

In the study, the team tested their approach by comparing two different dosing regimens for gentamicin, an antibiotic that’s commonly used in intensive care units. They used a microfluidic device that sandwiches a thin, permeable polyester membrane and a layer of cultured kidney cells between top and bottom compartments.

Ryan Oliver, Post-Doctorate Researcher, demonstrates use of a special microchip that can simulate different organs and parts of the body. Photo by: Joseph Xu

They then pumped a gentamicin solution into the top compartment, where it gradually filtered through the cells and the membrane, simulating the flow of medication through a human kidney. One test started with a high concentration that quickly tapered off, mimicking a once-daily drug dose. The other test simulated a slow infusion of the drug, using a lower concentration that stayed constant. Takayama’s team then measured damage to the kidney cells inside the device.

They found that a once-daily dose of the medication is significantly less harmful than a continuous infusion—even though both cases ultimately delivered the same dose of medication. The results of the test could help doctors better optimize dosing regimens for gentamicin in the future. Perhaps most importantly, they showed that a kidney on a chip device can be used to study the flow of medication through human organs.

“We were able to get results that better relate to human physiology, at least in terms of dosing effects, than what’s currently possible to obtain from common animal tests,” Takayama said. “The goal for the future is to improve these devices to the point where we’re able to see exactly how a medication affects the body from moment to moment, in real time.”

Takayama said the techniques used in the study should be generalizable to a wide variety of other organs and medications, enabling researchers to gather detailed information on how medications affect the heart, liver and other organs. In addition to helping researchers fine-tune drug dosing regimens, he believes the technique could also help drug makers test drugs more efficiently, bringing new medications to market faster.

Within a few years, Takayama envisions the creation of integrated devices that can quickly test multiple medication regimens and deliver a wide variety of information on how they affect human organs. PHASIQ, an Ann Arbor-based spinoff company founded by Takayama is commercializing the biomarker readout aspect of this type of technology in conjunction with the University of Michigan Office of Technology Transfer, where Takayama serves as a Faculty Innovation Ambassador.

University of Michigan researchers used a “kidney on a chip” to mimic the flow of medication through human kidneys. This enabled them to study the dosing regimen for a common intensive care drug.

The paper, published in the journal Biofabrication, is titled “Pharmacokinetic profile that reduces nephrotoxicity of gentamicin in a perfused kidney-on-a-chip.” Funding and assistance for the project was provided by the National Institutes of Health (grant number GM096040), the University of Michigan Center for Integrative Research in Critical Care (MCIRCC), the University of Michigan Biointerfaces Institute, the National Research Foundation of Korea and the Korean Association of Internal Medicine Research Grant 2015.

Ann Arbor – In an entirely new approach to treating asthma and allergies, a biodegradable nanoparticle acts like a Trojan horse, hiding an allergen in a friendly shell to convince the immune system not to attack it, according to new research from the University of Michigan and Northwestern University. As a result, the allergic reaction in the airways is shut down long term and an asthma attack prevented.

The technology can be applied to food allergies as well. The nanoparticle is currently being tested in a mouse model of peanut allergy, similar to food allergy in humans.

“Small quantities of allergen have been used to de-sensitize patients, and that delivering the allergen using emerging nanotechnologies can provide a more efficient and effective system” said senior author Lonnie Shea, the William and Valerie Hall Chair and Professor of Biomedical Engineering at the University of Michigan and adjunct professor at Northwestern.

The treatment can be applied to any allergy simply by loading the nanoparticle with the target allergen – from ragweed pollen to peanut protein.

In addition, the treatment makes use of an already FDA-approved material; the nanoparticles are composed of PLGA, a biopolymer that includes lactic acid and glycolic acid.

When the loaded nanoparticle is injected into the bloodstream of mice, the immune system sees the particle as innocuous debris. Then the nanoparticle and its hidden cargo are consumed by a macrophage, essentially a vacuum-cleaner cell.

“The vacuum-cleaner cell presents the allergen to the immune system in a way that says, ‘No worries, this belongs here,’” said Stephen Miller, another senior author on the study and the Judy Gugenheim Research Professor of Microbiology-Immunology at Northwestern University Feinberg School of Medicine. The immune system then shuts down its attack on the allergen, and the immune system is reset to normal.

The allergen, in this case egg protein, was administered into the lungs of mice who had been pretreated to be allergic to the protein and already had antibodies in their blood against it. After being treated with the nanoparticle, however, they no longer had an allergic response to the allergen.

The approach creates a more normal, balanced immune system by increasing the number of regulatory T cells – immune cells important for recognizing the airway allergens as normal – while turning off the allergy-causing Th2 T cells.

It’s the first time this method for creating tolerance in the immune system has been used in allergic diseases. The approach has been used in autoimmune diseases including multiple sclerosis and celiac disease in previous preclinical research at Northwestern, and a clinical trial using the nanoparticles to treat celiac disease is in development.

“The findings represent a novel, safe and effective long-term way to treat and potentially ‘cure’ patients with life-threatening respiratory and food allergies,” said Miller.

The asthma allergy study was in mice, but the technology is progressing to clinical trials in autoimmune disease. The nanoparticle technology is being developed commercially by Cour Pharmaceuticals Development Co. A clinical trial using the nanoparticles to treat celiac disease is in development.

The research was supported in part by grant EB-013198 from the National Institute of Biomedical Imaging and Bioengineering and grant NS-026543 from the National Institute of Neurological Disease and Stroke, both of the National Institutes of Health (NIH), the Dunard Fund and a predoctoral fellowship TL1R000108 from the NIH National Center for Research Resources and the National Center for Advancing Translational Sciences.

Michigan Engineering Professor Charles Cain outlines a new technique called "Histotripsy," which is a non-invasive ultrasonic approach for the treatment of benign disease and cancer. Cain says the knifeless surgical approach generates energetic microbubbles that oscillate very rapidly, almost like a "nano-blender." The procedure can be used for multiple applications, including treating newborn infants with heart defects, prostate patients and potentially diseases such as breast cancer.

Cain is the Founding Chair of Biomedical Engineering at the University of Michigan and the Richard A. Auhll Professor of Engineering. He and his research team have been developing the histotripsy technique for the last five years.

Every day, their baby stopped breathing, his collapsed bronchus blocking the crucial flow of air to his lungs. April and Bryan Gionfriddo watched helplessly, just praying that somehow the dire predictions weren’t true.

“Quite a few doctors said he had a good chance of not leaving the hospital alive,” says April Gionfriddo, about her now 20-month-old son, Kaiba. “At that point, we were desperate. Anything that would work, we would take it and run with it.”

Bioresorbable splint used for first time ever at the University of Michigan’s C.S. Mott Children’s Hospital, successfully stopped life-threatening tracheobronchomalacia, case featured in New England Journal of Medicine.

They found hope at the University of Michigan, where a new, bioresorbable device that could help Kaiba was under development. Kaiba’s doctors contacted Glenn Green, M.D., associate professor of pediatric otolaryngology at the University of Michigan.

Green and his colleague, Scott Hollister, Ph.D., professor of biomedical engineering and mechanical engineering and associate professor of surgery at U-M, went right into action, obtaining emergency clearance from the Food and Drug Administration to create and implant a tracheal splint for Kaiba made from a biopolymer called polycaprolactone.

On February 9, 2012, the specially-designed splint was placed in Kaiba at C.S. Mott Children’s Hospital. The splint was sewn around Kaiba’s airway to expand the bronchus and give it a skeleton to aid proper growth. Over about three years, the splint will be reabsorbed by the body. The case is featured today in the New England Journal of Medicine.

“It was amazing. As soon as the splint was put in, the lungs started going up and down for the first time and we knew he was going to be OK,” says Green.

Green and Hollister were able to make the custom-designed, custom-fabricated device using high-resolution imaging and computer-aided design. The device was created directly from a CT scan of Kaiba’s trachea/bronchus, integrating an image-based computer model with laser-based 3D printing to produce the splint.

“Our vision at the University of Michigan Health System is to create the future of health care through discovery. This collaboration between faculty in our Medical School and College of Engineering is an incredible demonstration of how we achieve that vision, translating research into treatments for our patients,” says Ora Hirsch Pescovitz, M.D., U-M executive vice president for medical affairs and CEO of the U-M Health System.

“Groundbreaking discoveries that save lives of individuals across the nation and world are happening right here in Ann Arbor. I continue to be inspired and proud of the extraordinary people and the amazing work happening across the Health System.”

Kaiba was off ventilator support 21 days after the procedure, and has not had breathing trouble since then.

“The material we used is a nice choice for this. It takes about two to three years for the trachea to remodel and grow into a healthy state, and that’s about how long this material will take to dissolve into the body,” says Hollister.

“Kaiba’s case is definitely the highlight of my career so far. To actually build something that a surgeon can use to save a person’s life? It’s a tremendous feeling.”

The image-based design and 3D biomaterial printing process can be adapted to build and reconstruct a number of tissue structures. Green and Hollister have already utilized the process to build and test patient specific ear and nose structures in pre-clinical models. In addition, the method has been used by Hollister with collaborators to rebuild bone structures (spine, craniofacial and long bone) in pre-clinical models.

Severe tracheobronchomalacia is rare. About 1 in 2,200 babies are born with tracheobronchomalacia and most children grow out of it by age 2 or 3, although it often is misdiagnosed as asthma that doesn’t respond to treatment.

Severe cases, like Kaiba’s, are about 10 percent of that number. And they are frightening, says Green. A normal cold can cause a baby to stop breathing. In Kaiba’s case, the family was out at a restaurant when he was six weeks old and he turned blue.

“Severe tracheobronchomalacia has been a condition that has bothered me for years,” says Green. “I’ve seen children die from it. To see this device work, it’s a major accomplishment and offers hope for these children.”

Before the device was placed, Kaiba continued to stop breathing on a regular basis and required resuscitation daily.

“Even with the best treatments available, he continued to have these episodes. He was imminently going to die. The physician treating him in Ohio knew there was no other option, other than our device in development here,” Green says.

Kaiba is doing well and he and his family, including an older brother and sister, live in Ohio

“He has not had another episode of turning blue,” says April. “We are so thankful that something could be done for him. It means the world to us.

A Michigan Engineering researcher has discovered that one common approach to growing blood vessels in tissues actually produces leaky tubes. He’s found a solution.

Could cancer be diagnosed with a simple blood test? A new chip can trap the one cancer cell in a billion normal cells.

Sunitha Nagrath and her lab developed the chip with other members of the Translational Oncology team, which seeks to produce technologies for improving cancer diagnosis and treatment that are ready for the clinic, to help real patients quickly. When the team runs a blood sample through the chip, it can catch breast, lung and pancreatic cancer cells. These cells can then be grown on the chip to learn more about the disease in a specific patient.

Sunitha Nagrath is an assistant professor of chemical engineering and biomedical engineering at the University of Michigan College of Engineering. Her research goal is to bring the next generation of engineering tools to patient care, especially in cancer. Her major focus of research is to develop advanced MEMS tools for understanding cell trafficking in cancer through isolation, characterization and study of circulating cell in peripheral blood of cancer patients. Research at The Nagrath Lab pertains to developing microfluidic devices for isolating and studying circulating tumor cells (CTCs) as related to metastasis.